Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by a loss of immune tolerance which results in the production of autoantibodies and immune complexes, and culminating in potentially fatal organ damage. Autoreactive B lymphocytes are at the center of this aberrant immune response, producing copious amounts of pathogenic autoantibodies. The first FDA drug in decades approved for the treatment of SLE directly targets and depletes B lymphocytes, making this approach appealing and warranting further exploration. B lymphocytes undergo the unique processes of class switch recombination (CSR) and somatic hypermutation, during which permanent DNA changes occur. These changes are due to double-stranded DNA breaks that are initiated by the molecule, AID, and subsequently repaired through homologous recombination. Using these genetic modifications, B lymphocytes are able to change the class of antibody they produce to more effectively respond to pathogenic invasion. In SLE, B lymphocytes actively undergo AID-initiated CSR to produce pathogenic autoantibodies. Our laboratory recently observed that AID is upregulated in the BXSB.Yaa mouse, which is arguably the most relevant animal model for human SLE. Most pathogenic antibodies produced in these mice originate from B-lymphocytes having undergone CSR. Since CSR is unique to B lymphocytes, therapeutic targeting of this process would provide a directed approach to eliminating only activated B lymphocytes producing pathogenic antibodies. The objective of this project is to investigate novel research strategies of therapeutic intervention in the BXSB.Yaa SLE mouse model that could be used in future translational studies aimed at improved therapeutic approaches for SLE patients. We hypothesize that AID-mediated CSR plays an important role in the pathogenesis of SLE, and that this process can be targeted for therapeutic intervention. To test our hypothesis, we propose two aims. Aim 1: Test if genetic deletion of Aicda (the gene encoding AID) abrogates the pathogenesis of SLE-like disease in the BXSB.Yaa mouse. We anticipate that SLE progression will be attenuated in these mice validating the targeting of this pathway for therapeutic intervention. Aim 2: Test whether administrations of novel therapeutic agents that prevent the repair of AID-induced DNA damage inhibit SLE-like disease progression in BXSB.Yaa mice. One therapeutic option is blocking the repair of AID-induced DNA breaks, which has been shown to result in B lymphocyte death. Mice will be treated with the small molecule inhibitors of DNA break repair, DIDS and C- 1523-1a, and monitored for disease progression. These compounds are members of a class of drugs currently being tested as a potential therapeutic for leukemia and lymphoma. The results of this study are expected to provide conclusive evidence that CSR plays a critical role in the pathogenesis of SLE and serves as a potential target for therapeutic intervention. Success of this approach in SLE would be novel for autoimmune disease therapy and would present future avenues for therapeutic exploration.